Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment

Pathological tau, a hallmark of Alzheimer's disease and other tauopathies, causes disruptions in neuronal activity and brain function. The exact mechanisms behind neuronal network dysfunction, however, are still unclear. In a recent study using human stem cell-derived neurons, researchers have discovered that a familial MAPT P301L mutation leads to neuronal network hyperexcitability.

This imbalance between excitation and inhibition is caused by subtype-specific tau pathology that alters the interactions between tau and other proteins differently in excitatory and inhibitory neurons. The study reveals that reducing excessive excitation or blocking the influx of calcium resulting from the enhanced P301L tau/AHNAK interaction in inhibitory neurons can alleviate the hyperexcitability.

The findings provide new insights into how disease-causing tau mutations disrupt the balance between excitation and inhibition in human neurons, ultimately contributing to network dysfunction.